Improved methods for providing compositions for controlled release of therapeutic agents are disclosed and exemplified in applicants' above-mentioned parent application Ser. No. 07/054,372. It has now been discovered that such novel compositions are uniquely suitable for treating dental diseases.
Drugs are conventionally administered orally or via injection, often at a site remote from the target. Over a relatively short period of time, the drug diffuses into the circulatory system of the patient and is distributed to the various organs and tissues, at least one of which is the intended target for the drug. The action of the drug on organs other than the target may result in undesirable side effects. Finally, the drug is metabolized or otherwise reversibly removed from the organism by excretion or chemical deactivation. When drugs are delivered orally or by injection by conventional non-sustained release formulations, the level and duration of availability of the drug cannot be controlled independently; only the size and frequency of the dose can be manipulated. Typically, there is an initially high concentration of available drug at the site of injection or in the circulatory system which then decreases gradually as the drug is distributed and consumed within the body of the patient.
In controlled or sustained delivery, a formulation of drug and a carrier is generally administered to the patient by ingestion or implantation. The carrier forms a drug reservoir that protects the stored drug from extraneous removal mechanisms and releases the drug to the biological reservoir at a predetermined rate. Controlled, sustained delivery of a drug prevents undesirable peaking of blood levels and makes the drug available at an optimum and substantially uniform concentration over an extended period of time. Only the released drug is subject to removal via metabolism and excretion. In the controlled sustained delivery method, there is potential for control of the drug release rate by factors inherent in the delivery package itself. Some of these inherent factors, such as the rate of hydrolysis of an absorbable polymer, or the rate of transdermal diffusion are in contrast to the externalized controls associated with classical delivery methods, e.g., rate of tablet intake, frequency of injections, etc. In accordance with prior methods, the maintanance of therapeutic blood levels of an antibiotic, for example, requires a fairly precise dosing of tablets. Though this may be uncomplicated for many adults, it may be difficult where gastric problems are present or for infants, the very infirm, or in veterinary work, such as with range animals.
Although the following discussion will emphasize the treatment of periodontal disease, the invention in its broadest aspects contemplates a system to treat abnormalities of the oral cavity amenable to administration of therapeutic agents generally. Such agents comprise, by way of illustration, antifungal agents, antibacterial agents, antibiotics, anti-inflammatory agents, immunosuppressive agents, immunostimulatory agents, dentinal densitizers, odor masking agents, immune reagents, anesthetics, antiseptics, nutritional agents, antioxidants, lipopolysaccharide complexing agents, peroxides, tissue growth factors, a mixture of any of the foregoing, and the like.
Periodontal disease is an all-inclusive term for a variety of clinical conditions that are forms of either gingivitis or periodontitis. Gingivitis is an inflammation of the gingiva (or gums) that can be associated with poor oral hygiene and/or the hormonal state of the patient. It is believed that gingivitis, if untreated, will develop into periodontitis. Periodontitis is a bacterial disease in which the infection has progressed to involve the oral tissues which retain the teeth in the jawbone. Periodontitis, if untreated, will eventually result in the loss of the affected teeth.
Although dental caries may be effectively treated with a combination of proper hygiene and fluoride, periodontal disease is often more refractile to treatment. This difference in amenability to treatment reflects the markedly different environments of the oral and periodontal cavities. The oral cavity is essentially an aerobic environment, which is constantly perfused by saliva. In contrast, the periodontal microenvironment is more anaerobic and is perfused by a plasma filtrate, known as the "crevicular fluid." The growth of microorganisms within this microenvironment may cause periodontal disease. Hence, the treatment of the disease is directed toward controlling this growth. As the periodontal disease becomes more established, the periodontal microenvironment becomes more anaerobic and the flow of crevicular fluid increases.
Efforts to treat periodontal disease have been impeded by several factors. Because the site of the bacterial infection is largely inaccessible to agents present in the oral cavity, antimicrobial agents provided to the oral cavity such as, for example, in a mouth wash are generally ineffective. The increased outward flow of crevicular fluid, which accompanies periodontal disease, has the effect of preventing therapeutic agents placed within the oral cavity from entering the periodontal pocket.
Ngai et al., U.S. Pat. No. 4,250,163 disclose a method of administering a broad range of medications to the oral cavity by means of a water-swellable and mucosa-adhesive polymeric matrix, which can be in the form of a tablet, powder or granules, and which is effective for times on the order of a few hours. These treatments are normally effective for periods of hours rather than days, and a course of treatment lasting one month would require the use of numerous tablets. Furthermore, this system is inappropriate for the treatment of periodontal disease because the drug is released into the saliva or oral mucosa, and does not penetrate the periodontal pocket to any significant extent. Buccal tapes, strips and similar disease forms suffer from the same disadvantages of inefficient delivery to the affected tissue.
Another disadvantage of such methods of dispensing drugs is that they may slip or be dislodged by the tongue or teeth, may be uncomfortable, and may interfere with the normal oral functions.
Oral systemic administration of antibiotics has been shown to be a useful method of controlling the subgingival flora. However, because of side effects such as those of the digestive system, for example pseudomembraneous colitis, anorexia, nausea and diarrhea, biochemical abnormalities such as thrombocytopenia and eosinophilia. Oral systematic administration has had only limited use in treating periodontal disease. Oral systemic therapy required frequent dosing, so patient compliance is frequently a problem.
Recent developments in the art are directed toward delivering the therapeutic agent directly to the periodontal pocket, in some cases in a controlled release formulation. In general, administration of agents directly to the pocket permits higher local drug concentrations than can be achieved by systematic administration. Doses in the latter case are limited by systematic side effects. Also some agents, such as tissue growth factors must be administered directly to the target site, i.e. the periodontal pocket.
Goodson, U.S. Pat. No. 4,175,326, describes the use of a drug-filled polymer hollow fiber. This delivery system is tied around a tooth and gently pressed below the margin of the gingiva so that it resides in the periodontal pocket, and is capable of delivering an effective dose of 2.5 micrograms of tetracycline per day per periodontal pocket for a prolonged period of a week or more.
It has been reported that tetracycline can be incorporated in polymethyl methacrylate or ethylene vinyl acetate to prepare a solid composition in the form of strips or fibers to be used for topical application to a lesion in the oral cavity, such as periodontal pockets (J. Periodontol., 53(11), 693-699 (1982) and 54(10), 575-579 (1983)).
An acrylic strip, formed from ethyl cellulose impregnated with metronidazole, is disclosed by Loesche in U.S. Pat. No. 4,568,538.
Another strip, employing a water soluble polymer of a particular elasticity and viscosity, is disclosed by Suzuki et al. in U.S. Pat. No. 4,569,837.
Although these devices may be able to dispense an appropriate drug for a time span of a week or more, they are inappropriate to widespread use because they are difficult and time consuming to apply and may be dislodged by the patient during normal oral functions.
Baker, European Patent Application No. 0244118, describes therapeutic agent containing microparticles suspended in a liquid carrier, but when put into the periodontal pocket they are prone to wash out since they do not adhere to the involved tissue.
Hasegawa et al., U.S. Pat. No. 4,701,320, disclose a stable minocycline containing gel composition for treating periodontal diseases by direct application. The compositions of Hasegawa et al. reduce bacteria in the periodontal pocket within one day of treatment, but then after one week the bacterial count increases substantially indicating a short term effect.
On the other hand, the formulation discovered by the applicants, and the subject matter of this invention, has been specifically developed to deliver therapeutic agents, e.g., minocycline, doxycycline, and continuously for periods up to two weeks, thereby providing therapeutically effective drug levels over a substantially longer period of time than taught by Hasegawa et al., and without the manipulative drawbacks of the fibers, and polymer strips.
In the above-mentioned copending applications of two of the three applicants herein, a phase separation process is used to microencapsulate therapeutic agents in a biodegradable polymer matrix, the resulting product comprising microparticles of the agent in the polymer. The microparticles described in the copending application comprise a sustained release delivery system for systemic administration to patients in need of treatment.
It has now been found that with optional modifications, such compositions are particularly useful for local administration to the periodontal pocket for treating dental diseases. The formulation of this invention is adapted to be administered as a dry powder which absorbs water upon administration and becomes tacky. This promotes adhesion to the tissues forming the periodontal pocket. Thus, no additional means to promote adhesion in the periodontal pocket are necessary with this invention. Inactive components are polymers which biodegrade and do not require removal from the crevicular pocket. Degradation products of the preferred polymers are acidic and are capable of providing the optimum pH inside the microparticles for stability of antibiotics certain tetracyclines, such as minocycline, doxycycline, and the like. As will be shown, the formulations of this invention provide drug levels in crevicular fluid for a longer period of time than, for example, gel type formulations of Hasegawa et al.